Chacoo



aware A -7-ACYLOXY-9,ll-EPOXY-STEROIDS AND PROCESSES F PREPARING THEMJohn M. Chemerda, Metuchen, N. 3., assignor to Merck & Co., Inc.,Rahway, N. L, a corporation of New Jersey N0 Drawing. Application August2, E51, Serial No. 240,052

17 Claims. (Cl. 260-23955) This invention is concerned generally withsteroid compounds having an oxygen atom attached to the carbon atom inthe ll-position of the molecule, and with processes for preparing thesell-oxygenated steroid compounds. More particularly, it relates to A-7-keto-11- (keto, hydroxy or acyloxy)-cyclopentanopolyhydrophenanthrenecompounds and with processes for preparing these compounds starting withthe corresponding A 9(11) 7 keto-cyclopentanopolyhydrophenanthrenecompound. The A -7-keto-11-(keto, hydroxy or acyloxy)-cyclopentanopolyhydrophenanthrene compounds thus obtained are valuableas intermediates in the synthesis of steroid hormones having an oxygenatom attached to the ll-carbon atom, such as the adrenal hormones,corticosterone, cortisone and Compound F.

The A -7-keto-11-(keto, hydroxy oracyloXy)-cyclopentanopolyhydrophenanthrene compounds, subject of thepresent invention, have at rings B and C the following chemicalstructures:

wherein R is a keto, hydroxy or acyloxy radical.

These A -7-keto-11-(keto, hydroxy or acyloxy)-cyclopentanopolyhydrophenanthrene compounds can be {are pared as follows:a A -7-keto-cyclopentanopolyhydrophenantbrene compound (Compound 1hereinbelow), a A -7 keto-cyclopentanopolyhydrophenanthrene compound(Compound 2), or a mixture of these compounds, is reacted with anacylating agent to produce the corresponding enol acylate, that is, theA -7-acyloxycyclopentanopolyhydrophenanthrene compound (Compound 3); thelatter compound is treated with an organic per-acid, whereby the doublebond connecting the 9 and ll-carbon atoms is replaced by a 9,11-epoxidelinkage, thereby forming the corresponding A"-7-acyloxy-9,l1- epoxycyclopentanopolyhydrophenanthrene compound (Compound 4). This compoundis then subjected to the action of a mild hydrolytic agent, whereuponhydrolysis of the enol acylate substituent occurs without afiectingother hydrolyzable substituents in the molecule, to produce thecorresponding 7-keto-9,11-epoxy-cyclopentanopolyhydrophenanthrenecompound (Compound 5). This compound or, alternatively, its precursorthe A 7-acyloxy-9,11-epoxy-cyclopentanopolyhydrophenanthrene compound,is converted by reaction with an alcoholic solution of an alkali metalhydroxide to the cor 2,734,897 Patented Feb; 14', 195a responding A -7-l eto-ll hydroxy cyclopentanopolyhy drophenanthrene compound (Compound6). A? 7 keto-l1-hydroxy-cyclopentanopolyhydrophenarithrene compound, orits precursor the 7-keto-9,'1l-epoxy-cyclo pentanopolyhydrophenanthrenecompound, is then reacted with an acylating agent thereby forming thecorresponding A -7-keto-1l-acyloxy-cyclopentanopolyhydrophenanthrenecompound (Compound 7). Where it isdesired to have a keto substituent inthe ll-posi'tion, the 7-keto 9,11 epoxycyclopentanopolyhydrophenanthrene' com pound (Compound 5), isreacted'with a strong oxidizing agent such as chromic acid therebyforming the corresponding A7,11-diketo-cyclopentanopolyhydrophenanthrene compound (Compound 8 Thereactions indicated hereinabove may be chemically represented, insofaras rings 3 and C are concerned, as follows:

Compound 3 Compound 4 ild Alcoholic ydrolyzing alkali metal i! agenthydroxide \1 mil? Distal \lj/ hydroxide Compound 5 Compound 6 StrongAcylating oxidizing agent Acylating agent agent Compound 8 Compound 7wherein R represents an acyl radical.

' The A -7 -'keto cyclopentanopolyhydrophenantbrene compounds and A-7-keto-cyclopentanopolyhydrophenanthrene compounds which we ordinarilyemploy as starting materials in carrying out the presently inventedprocess are those having a sterol side chain attached to the carbon atomin the 17-position of the molecule such as A -7-keto-ergostadiene, A-7-keto-ergostadione, A -3-hydroxy-7-keto-ergostadiene, A-3-hydroxy-7-keto-ergostadiene, A -7-keto cholestene, A7-keto-cholestene, A 3-hydroxy 7 keto-cholestene, M-3-hydroxy-7-keto-cholestene, A -3-hydroxy 7 ketoastig'mastadiene, A-3-hydroxy-7keto-stigmastadiene, a bilel acid side chain attached to the17-carbon atom such as A -3-hydroxy-7-ket0-cholenic acid, A3-hydroxy-7-keto-cholenic acid, A -3-hydroxy-7-ketoallocholenic acid, A-3-hydroxy-7-keto-allocholenic acid, a degraded bile acid side chainattached to the 17- carbon atom such as A-3-hydroxy-7-keto-bisnorcholcnic acid, A 98-hydroxy-7-keto-bisnorcholenic acid, [t -3-hydroxy-7-keto-bisnorallocholenic acid, A -3-hydroxy-7-keto-bisnorallocholenic acid, a l7-carboxyl substituent such as A-7-keto-etiocholenic acid, A -7-keto-etio,- cholenic acid, A-7-keto-etioallocholenic acid, M -7- keto-etioallocholenic acid, a17-acetyl substituent such as A 3-hydroxy-7-keto-pregnene, A-3-hydroxy-7-ketoallopregnene, a sapogenin side chain such as A-7-ketodehydrotigonenin, A -7-keto-dehydrotigogenin, as well as A or A-7-keto-cyclopentanopolyhydrophenanthrene compounds having a hydroxysubstituent in the 3- position of the molecule esterified by an acylsubstituent, and the like.

In preparing these A or -7-keto-cyclopentanopolyhydrophenanthrenecompounds, we ordinarily start with the corresponding A-cyclopentanopolyhydro phenanthrene compounds, certain of which, such asergosterol D and 3-acyloxy derivatives thereof, are described in theprior art. Other A -cyclopentanopolyhydrophenanthrene compounds can beprepared, starting with readily available A-cyclopentanopolyhydrophenanthrene compounds such as cholesterol, bytreating said A cyclopentanopolyhydrophenanthrene c o m p o u n d(Compound 9 hereinbelow) with bromo-succinimide, reacting the resultingA -7-bromo-cyclopentanopolyhydrophenanthrene compound (Compound 10) witha tertiary amine to form the corresponding A-cyclopentanopolyhydrophenanthrene compound (Compound 11), reacting thiscompound with hydrogen in the presence of Raney nickel catalyst therebyselectively reducing the unsaturated linkage attached to the carbon atomin the 5-position to form the corresponding A'cyclopentanopolyhydrophenanthrene compound (Compound 12) and bringingsaid A -cyclopentanopolyhydrophenanthrene compound into intimate contactwith a solution of mercuric acetate in acetic acid thereby producing thecor- Artiar'y ,1 amino l |l ll Raney nickel Compound 11 Compound 12 13:33? I i Q \I l V Compound 13 T h e s' e 13 l-cyclopentanopolyhydrophenanthrene compounds can then be converted tothe desired A or '-7-keto-cyclopentanopolyhydrophenanthrene compounds,(utilized as starting materials in the presently invented process). asfollows: the A' -cyclopentanopolyhydrophenanthrene compound (Compound13) is reacted with osmium tetroxide and the intermediate osmate esteris hydrolyzed, preferably by treatment with aqueous sodium sulfite, toform the corresponding A 7,S-dihydroxy-cyclopentanopolyhydrophenanthrenecompound (Compound 14) and/or A-9,11-dihydroxy-cyclopentanopolyhydrophenanthrene compound (Compoundl5). Either of these compounds, or a mixture thereof, is

then reacted with an aqueous acidic solution at a temperature betweenabout room temperature and 100 C. to produce a mixture of the desired A-7-keto-cyclopentanopolyhydrophenananthrene compound (Compound 1) andA901) 7 keto-cyclopentanopolyhydrophenanthrene compound (Compound 2);

Alternatively, the A -cyclopentanopolyhydrophenanthrene compound can bereacted with perbenzoic acid to form the corresponding A-9,1l-epoxy-cyclopentanopolyhydrophenanthrene compound (Compound 16)and/or the corresponding A -7,8-epoxy-cyclopentanopolyhydrophenanthrenecompound (Compound 17). Either of these compounds or a mixture thereofcan be reacted with an aqueous acidic solution at a temperature 7between room temperature and 100 C. to form the deresponding A'-cyclopentanopolyhydrophenanthrene Compound 0 CompoundilOBrornosuccinimide sired A 0r -7-keto-cyclopentanopolyhydrophenanthrenecompound.

If desired, the A -cyclopentanopolyhydrophenanthrene epoxide compoundcan be suspended in a liquid medium such as an alkanoic anhydride,xylene, and the like, and the suspension heated at a temperature ofabout 150 C. thereby forming directly the corresponding Am 9-7-keto-cyclopentanopolyhydrophenanthrenc compound, (Compounds 1 and 2).Instead of isolating the A 9 -7-keto-cyclopentanopolyhydrophenanthrenecompound, the reaction mixture can 'be heated,

without purification, with an alkanoyl chloride thereby forming thecorresponding enol acylate,'the'A7-acyloxy-cyclopentanopolyhydrophenanthrene compound (Compound 3 shownin column 2). indicated hereinabove' may be chemically represented Thereactions eaten I (1) Osmium Tetroxide i (2) Hydrolyzing Agent Compound13 Perbenzoie DO Aqueous Acid or alkanoic anhydride at 150 0.

Compound 17 Compound 16 Alkanoic Anhydride alkanoyl chloride Compound 14Compound 1 The A' 7 acyloxy cyclopentanopolyhydrophenanthrene compoundis then reacted with an organic Ho Compound 15 Aqueous Act Compound 2The 11 -7-keto-cyclopentanopolyhydrophenanthrene starting material isreacted with an acylating agent to produce the corresponding enolacylate, the A1901) 7 acyloxycyclopentanopolyhydrophenanthrene compound.This acylation reaction is ordinarily carried out by bringing the A-7-keto-cyclopentanopolyhydrophenanthrene compound into intimate contactwith said acylating agent, preferably a lower alkanoic anhydride such asacetic anhydrlde, propanoic anhydride, and the like, in the presence ofa catalyst such as acetyl chloride, p-toluene sulfonic acid, pyridineand the like, thereby forming said A7301) 7acyloxy-cyclopentanopolyhydrophenanthrene compound such as M90932 7acyloxy-' ergostatriene, A 3,7 diacyloxy ergostatriene, A-3,7-dialkanoxy-ergostatriene, A -3,7 diacetoxy-ergostatriene, A7301) 7acyloxy-cholestadiene, A1901) 3,7 diacyloxy-chloestadiene, A1901) 3,7dialkanoxy-cholestadiene, A1911!) 3,7 diacetoxy cholestadiene, A-3,7-diacyloxy-stigrnastatriene, M 3,7 dialkanoxy stigmastatriene, A 3,7diacetoxy stigmastatriene, A1901) 3,7 diacyloxy choladienic acid, 41 3,7dialkanoxy choladienic acid, A 3,7 diacetoxy choladienic acid, M1901)3,7 diacyloxy allocholadienic acid, A1901) 3,7 dialkanoxyallocholadienic acid, A1901) 3,7 diacetoxy-allocholadienic acid, A-3,7-diacyloxy-bisnorcholadienic acid, A -3,7-dialkanoxy-bisnorcholadienic acid, A -3,7-diacetoxybisnorcholadienicacid, A 3,7 diacyloxy bisnor allocholadienic acid, A7301) 3,7 dialkanoxybisnorallocholadienic acid, A1901) 3,7 diacetoxy bisnorallocholadienicacid, A 3,7 diacyloxy etiocholadienic acid, A1901) 3,7 diacyloxyetioallocholadienic acid, A 3,7 diacyloxy pregnadiene, A1901) 3,7dialkanoxy pregnadieue, A1901) 3,7 diacetoxy pregnadiene, A1901) 3,7diacyloxy allopregnadiene, A7301) 3,7 dialkanoxy allopregnadiene, A 3,7diace'toxy allopregnadiene, A7301) 7 acyloxy dehydrotigogenin acylate, A7 alkanoxy dehydrotigogenin alkanoate, A 7 acetoxy dehydrotigogeninacetate, and the like.

Gompound3 per-acid such as perbenzoic acid, perphthalic acid, and

following: A' 7 acyloxy 9,11 epoxy ergostadiene,

A 2 3,7 diacyloxy 9,11 epoxy ergostadiene, A 3,7 dialkanoxy 9,11 epoxy-ergostadiene, A7722 3,7 diacetoxy 9,11 epoxy ergostadiene, A 7 acyloxy9,11 epoxy cholestene, A 3,7 diacyloxy 9,11 epoxy cholestene, A 3,7dialkanoxy 9,11 epoxy cholestene, A 3,7 diacetoxy 9,11 epoxy cholestene,A7122 3,7 diacyloxy 9,11 epoxy stigmastadiene, A7122 3,7 dialkanoxy 9,11epoxy stigmastadiene, A 3,7 diacetoxy 9,11 epoxy stigmastadiene, A 3,7diacyloxy 9,11 epoxy cholenic acid, A 3,7 dialkanoxy 9,11 epoxy cholenicacid, A 3,7 diacetoxy 9,11 epoxy cholenic acid, A 3,7 diacyloxy 9,11epoxy allocholenic acid, A 3,7 dialkanoxy 9,11 epoxy allocholenic acid,A 3,7 di'acetoxy 9,11

epoxy allocholenic acid, A 3,7 diacyloxy 9,11

epoxy bisnorcholenic acid, A 3,7 dialkanoxy 9,11 epoxy bisnorcholenicacid, A 3,7 diacetoxy 9,11 epoxy bisnorcholenic acid, n 3,7 diacyloxy9,11 epoxy bisnorallocholenic acid, A 3,7 dialkanoxy 9,11 epoxybisnorallocholenic acid, A 3,7 diacetoxy- 9,11 epoxy bis'norallocholenicacid, A' 3,7 diacyloxy-- 9,11 epoxy etiocholenic acid, A 3,7 diacyloxy9,11-

epoxy etioallocholenic acid, A 3,7 diacyloxy 9,11- epoxy pregnene, A 3,7dialkanoxy 9,11 epoxy-- pregnene, A"'- 3,7 diacetoxy 9,11 epoxypregnene, A 3,7 diacyloxy 9,11 epoxy allopregnene, A 3,7-- dialkanoxy9,11 epoxy allopregnene, A 3,7 di--- acetoxy 9,11 epoxy allopregnene, Al7 acyloxy 9,11 epoxy deh drotigo eni'n ae lategn' 7' alkanoxw- 7 9,11epoxy dehydrotigogenin alkanoate, A! 7 acetoxy 9,11 epoxy edehydrotigogenin acetate, and the like.

The A 7 acyloxy 9,11 epoxy cyclopentanopolyhydrophenanthrene compound isthen subjected to the action of a mild hydrolytic agent, whereuponhydrolysis of the enol acylate substituent occurs without afiectingother hydrolyzable substituents in the molecule. This partial hydrolysisreaction is conveniently conducted by reacting said A 7 acyloxy 9,11epoxy cyclopentanopolyhydrophenanthrene compound, at approximately roomtemperature, with water or preferably with an aqueous solution of awater-miscible solvent such as an aqueous solution of acetone, anaqueous solution of a lower aliphatic alcohol such as methanol, ethanol,and the like. The product obtained by the selective hydrolysis of theenol acylate substituent of said A 7 acyloxy- 9,11 epoxycyclopentanopolyhydrophenanthrene compound is the corresponding7-keto-9,lI-epoxy-cyclopentanopolyhydrophenanthrene compound such as A7- keto 9,11 epoxy ergostene, A 3 acyloxy 7 keto- 9,11 epoxy ergostene,A 3 alkanoxy 7 keto 9,11- epoxy ergostene, A 3 acetoxy 7 keto 9,11epoxyergostene, 7 keto 9,11 epoxy cholestane, 3 acyloxy- 7 keto 9,11epoxy cholestane, 3 alkanoxy 7- keto 9,11 epoxy cholestane, 3 acetoxy 7keto- 9,11 epoxy cholestane, A e 3 acyloxy 7 keto- 9,11 epoxys'tiginastene, A 3 alkanoxy 7 keto 9,11 epoxy stigmastene, A 3 acetoxy 7keto- 9,11 epoxy stigmastene, 3 acyloxy 7 keto 9,11 epoxy cholanic acid,3 alkanoxy 7 keto 9,11- epoxy cholanic acid, 3 acetoxy 7 keto 9,11epoxycholanic acid, 3 acyloxy 7 keto 9,11 epoxy allocholanic acid, 3alkanoxy 7 keto 9,11 epoxy allocholanic acid, 3 acetoxy 7 keto 9,11epoxy allocholanic acid, 3 acyloxy 7 keto 9,11 epoxy bisnorcholanicacid, 3 alkanoxy 7 keto 9,11 epoxy bisnorcholanic acid, 3 acetoxy 7 keto9,11 epoxybisnorcholanic acid, 3 acyloxy 7 keto 9,11epoxybisnorallocholanic acid, 3 alkanoxy 7 keto 9,11- epoxybisnorallocholanic acid, 3 acetoxy 7 keto- 9,11 bisnorallocholanic acid,3 acyloxy 7 keto 9,11- epoxy etiocholanic acid, 3 acyloxy 7 keto 9,11-epoxy etioallocholanic acid, 3 acyloxy 7 keto 9,11- epoxy pregnane, 3alkanoxy 7 keto 9,11 epoxypregnane, 3 acetoxy 7 keto 9,11 epoxypregnane, 3 acyloxy 7 keto 9,11 epoxy allopregnane, 3- alkanoxy 7 keto9,11 epoxy allopregnane, 3 acetoxy 7 keto 9,11 epoxy allopregnane, 7keto 9,11- epoxy tigogenin acylate, 7 keto 9,11 epoxy tigogeninalkanoate, 7 keto 9,11 epoxy tigogenin acetate, and the like.

This 7-keto-9,1l-epoxy-cyclopentanopolyhydrophenanthrene compound, oralternatively, its precursor the A 7- acyloxy 9,11 epoxycyclopentanopolyhydrophenanthrene compound is then reacted with analcoholic solu tion of an alkali metal hydroxide, such as ethanolicpotassium hydroxide, methanolic potassium hydroxide, methanolic sodiumhydroxide, and the like, thereby hydrolyzing the 9,11-epoxy linkage, aswell as other hydrolyzable substituents present in the molecule. Thishydrolysis reaction is conveniently carried out by dissolving the 7-keto9,11 epoxy cyclopentanopolyhydrophenanthrene compound or the A-7-acyloxy-9,1l-epoxy-cyclopentanopolyhydrophenanthrene compound in analcoholic solution of the alkali metal hydroxide and heating theresulting solution at the reflux temperature. When a A-7-acyloxy-9,ll-epoxy cyclopentanopolyhydrophenanthrene compound or a7-keto-9,ll-epoxycyclopentanopolyhydrophenanthrene compound is subjectedto these conditions of hydrolysis, there is obtained the corresponding A-7-keto-11-hydroxy cyclopentanopolyhydrophenanthrene compound such as A7 keto 11 hydroxyergostadiene, M 3,11-dihydroxy-7-keto-ergostadiene, A-7-keto-1l-hydroxycholestene, rts) 3,11-dihydroxy- 7-ketocholestene, A-3,11-dihydroxy-7-keto-cholestene,

A 2 -3,11=dihydroxy-Lketo-stigmastadiene, A 3,11-dihydroxy-7-keto-cholenic acid, A 3,1l-dihydroxy-7- keto-allocholenicacid, A -dihydroxy-7-keto-bisnorcholenic acid, A -3,11-dihydroxy-7-ketobisn0rallocholenic acid, A -3,11-dihydroxy-7-keto-etiocholenic acid, 113,11-dihydroxy-7-keto-etioallocholenicacid, N -3,11, dih ydroxy 7 ketopregnene, A 3,11 dihydroxy- 7 keto allopregnene, A-7-keto-1l-hydroxy-dehydrotigogenin, and the like.- 1 p This A-keto-l1-hydroxy-cyclopentanopolyhydrop'nenanthrene compound, or itsprecursor the 7-keto-9,11- epoxycyclopentanopolyhydrophenanthrenecompound, is then reacted with an acylating agent to produce thecorresponding A -7-keto-11-acyloxy-cyclopentanopolyhydrophenanthrenecompound. The acylation'of the A -7- keto l1hydroxy-cyclopentanopolyhydrophenanthrene compound is convenientlycarried out utilizing a lower aliphatic acid anhydride, such as aceticanhydride, propionic anhydride, and the like, in the presence of atertiary amine such as pyridine, although other acylating agents can beused if desired. The acylation of the precursor, the 7 keto9,11-epoxy-cyclopentanopolyhydrophenanthrene compound, is ordinarilyconducted utilizing a lower aliphatic anhydn'de such as aceticanhydride, propionic anhydride and the like, in the presence of analkanoyl halide preferably carried out at approximately room temperaturealthough higher or lower temperatures can be employed if desired. The A-7-keto-1 l-acyloxy-cyclopentanopolyhydrophenanthrene compounds obtainedaccording to this acylatiou procedure include the following: A 7 keto-1lacyloxy ergostadiene, A 3,11 diacyloxy-7-keto-ergostadiene, A 3,11dialkanoxy-7-ketoergostadiene, d 3,11-diacetoxy-7-keto-ergostadiene, A-7-keto-1l-acyloxy-cholestene, A -3,l1-diacyloxy-7- keto-cholestene, A3,1l-diacetoxy-7-keto-cho1estene, A 3,11diacyloxy-7-keto-stigmastadiene, A 3,1ldialkanoxy-7-keto-stigmastadiene, M -3,11 diacetoxy-7-ketostigmastadiene, A -3,11-diacy1oxy-7-ketocholenic acid, M-3,11-dialkanoxy-7-keto-cholenic acid, A -3,1l-diacetoxy 7 keto-cholenicacid, A -3,11- diacyloxy-7-keto-al1ocholenic acid, A -3,1l-dialkanoxy-7-keto-allocholenic acid, M -3,11-diacetoxy-7-keto-allocholenic acid, o-3,11-diacyloxy-7-keto-bisnorcholenic acid, A -3,11-dialkanoxy 7 ketobisnorcholenic acid, o -3,11-diacetoxy-7-keto-bisnorcholenic acid, d-3,11- diacyloxy-7-keto-bisnorallocholenic acid, A-3,11-dialkanoxy-7-keto-bisnoral1ocholenic acid, A-3,11-diacetoxy-7-keto-bisnorallocholenic acid, A -3,1l-diacyloxy-7-keto-etiocholenic acid, A 3,11 diacyloxy 7 ketoetioallocholenic acid,A -3,1l-diacyloxy-7-keto-pregnene, A -3,11-dialkanoxy-7-keto-pregnene,AN -3,11- diacetoxy-7-keto-pregnene, M-3,11-diacyloxy-7-keto-allopregnene, A 3,11 dialkanoxy7-keto-allopregnene, A -3 ,1 1-diacetoxy-7-keto-allopregnene, A-7-keto-11- acyloxy-dehydrotigogenin acylate, A 7-ketoll-alkanoxy-dehydrotigogenin alkanoate, A-7-kcto-11-acetoxydehydrotigogenin acetate, and the like.

As set forth hereinabove, where it is desired to have an ll-ketosubstituent in the molecule, the7-keto-9,11-epoxycyclopentanopolyhydrophenanthrenc compound is reactedwith a strong oxidizing agent, such as chromic acid, thereby forming thecorresponding M -7,1l-diketo-cyclopentanopolyhydrophenanthrene compound.This oxidation reaction, where chromic acid is used as the oxidizingagent, is conveniently carried out by dissolving the 7-keto- 9,11 epoxycyclopentanopolyhydrophenanthrene compound in acetone, adding to theresulting solution a solution containing chromic acid dissolved inaqueous sulfuric acid, and allowing the mixture to react atsubstantially room temperature for a period of approximately 1 hour. Inaccordance with this procedure, there is obtained the desired A-7,1l-diketo-cyclopentanopolyhydrophenanthrene compound such as A"-7,11-diketoergostadiene, A -3-acyloxy-7,lLdiketo-ergostadiene,

wise

A -3-alkanoxy-7-diketo-ergostadiene, A -3- acetoxy7,1l-diketo-ergostadiene, A -7,11-diketo-cholestene, A-3-acyloxy-7,1l-diketo-cholestene, A -3-alkanoxy-7 ,1l-diketo-cholestene, A -3-acetoxy-7,1 l-dilretocholestene, A-3-acyloxy-7,1l-diketo-stigmastadiene, A -3-alkanoxy-7,1l-diketo-stigmastadiene, A -3- acetoxy-7,1 l-diketo-stigmastadiene, A-3-acyloxy-7,11- diketo-cholenic acid, A-3-alkanoxy-7,1l-diketo-cholenic acid, A -3-acetoxy-7,1l-diketo-cholenicacid, A -3- acyloxy-7,1l-diketo-allocholenic acid, A -3-alkanoxy-7,ll-diketo-allocholenic acid, A -3-acetoxy-7,l1-diketoallocholenic acid,A 3 acyloxy 7,11 diketo-bisnorcholenic acid, A-3-alkanoxy-7,1l-diketo-bisnorcholenic acid, A 3 acetoxy7,1l-diketo-bisnorcholenic acid, A-3-acyloxy-7,1l-diketo-bisnorallocholenic acid, A3-alkanoxy-7,l1-diketobisnorallocholenic acid, A-3-aceterry-7,1l-diketo-bisnorallocholenic acid, A -3-acyloxy-7,ll-diketo-etiocholenic acid, A -3-acyloxy-7,11 diketoetioallocholenicacid, A -3 -acyloxy-7,ll-diketo-pregnene, A-3-alkanoxy-7,1l-diketo-pregnene, A -3-acetoxy-7,1l-diketo-pregnene, A-3-acyloxy-7,1 l-diketo-allo-pregnene, A 3alkanoxy-7,1l-diketo-allopregnene, A-3-acetoxy-7,1l-diketo-allopregnene, A -7,11,diketo-dehydrotigogeninacylate, A -7,11-diketo-dehydrotigogenin alkanoate, A-7,1l-diketo-dehydrotigogenin acetate, and the like.

The A 3,11 dihydroxy 7 keto cyclopentanopolyhydrophenanthrene compounds(Compound 6 hereinabove) are readily converted to steroid hormoneshaving an oxygen atom attached to the ll-carbon atom as follows: The h-3,11-dihydroxy-7-keto-cyclopentanopolyhydrophenanthrene compound isreacted with zinc and acetic acid thereby forming the corresponding3,11- dihydroxy 7 keto cyclopentanopolyhydrophenanthrene compound, whichis heated with a diethylene glycol solution of hydrazine and potassiumhydroxide to produce the corresponding3,11-dihydroxy-cyclopentanoperhydrophenanthrene compound; this3,l1-dihydroxy-cyclopentanoperhydrophenanthrene compound is then treatedaccording to known methods (the exact method of treatment depending uponthe side chain attached to the 17-carbon atom) to convert the organicsubstituent attached to the 20-carbon atom to a keto radical thusforming the corresponding 3,11-dihydroxy- ZO-keto-pregnane. (Forexample, where the side chain attached to the 17-carbon atom is thatpresent in the bile acid, bisnorallocholanic acid, the3,11-dihydroxybisnorallocholanic acid is esterified, the methyl- 3,11-dihydroxy-bisnorallocholanate is reacted with phenyl magnesium iodide toform 3,1l-dihydroxy-ZO-allopregnanyl-diphenyl-carbinol; the lattercompound is reacted with acetic anhydride to produce3,11-diacetoxy-alloetiocholanyl-methyl-diphenyl-ethylene, and thiscompound is treated with ozone to form 3,11-diacetoxy-20- ketoallopregnane.) This 3,11 diacetoxy 20 ketoallopregnane (obtained asdescribed above starting with 3,11-dihydroxy-bisnorallocholanic acid, orif preferred, by degrading the side chain of some other3,11-dihydroxy-cyclophentanoperhydrophenanthrene compound) is thenreacted with an acetic anhydride in the presence of p-toluene sulfonicacid catalyst thereby forming the corresponding A-3,11,20-triacetoxy-pregnene; this compound is reacted with perbenzoicacid to form 3,11- diacyloxy-l7-hydroxy-20-keto-allopregnane; the lattercompound is then reacted with bromine followed by sodium acetate therebyforming the corresponding 3,11,20 triacetoxy l7 hydroxy 20 ketoallopregnane which, upon reaction with a hydrolyzing agent followed by apartial esterification, yields the corresponding 3,11,17 trihydroxy 20keto 21 acetoxyallopregnane; the3,11,l7-trihydroxy-20-keto-2l-acetoxyallopregnane is then reacted withchromic acid thereby forming 3,11,20 triketo 17 hydroxy 21acetoxyallopregnane which is reacted with two molecular equivalents ofbromine followed by rearrangement to produce 10, the corresponding 2,4dibromo 3,11,20 triketo 17- hydroxy-2l-acetoxy-allopregnane; thiscompound is reacted with a dehydrohalogenating agent and a reducingagent to form cortisone acetate, i. e. A -3,11,20-triketo-17-hydroxy-2l-acetoxy-pregnene.

The following examples illustrate methods of carry ing out the presentinvention, butit is to be understood that these examples are given forpurposes of illustration and not of limitation.

Example 1 Four hundred milligrams of A -3-hydroxy-7-ketoergostadiene(which can be prepared, starting with ergosterol D acetate, inaccordance with the procedure set forth in columns 4 and 5 hereinbeforeand described more particularly in a copending application of thepresent applicant, Serial No. 240,051, filed August 2, 1951), were mixedwith 1 cc. of acetic anhydride and 1 cc. of acetyl chloride, and themixture was heated under reflux for a period of about one hour. Thesolvents were evaporated from the reaction mixture to give crude A-3,7-diacetoxy-ergostatriene which was obtained as a yellow gum; A max.237 mu,

This material was subjected to further purification by chromatography togive a product having an extinction coeificient of 320.

Example 2 A mixture containing 1 gram of A -3-hydroxy-7-keto-ergostadiene, 20 cc. of acetic anhydride and 20 cc. of acetylchloride was heated under reflux for a period of about 1 hour. Thesolvents were evaporated from the reaction mixture in vacuo to givecrude A' -3,7- diacetoxy-ergostatriene. This material was dissolved in25 cc. of benzene, and to this solution was added 15.5 cc. of a solutionof perbenzoic acid in benzene having a normality of 0.375. The resultingsolution was allowed to stand at room temperature for a period of about12 hours, the reaction solution was extracted with an aqueous solutionof sodium hydroxide, then with water, and

dried. The dry benzene solution was evaporated in vacuo to give crude A-3,7-diacetoxy-9,11-epoxy-ergostadiene as a residual gum.

This material was subjected to chromatographic purification utilizingether-petroleum other as the eluting solvent to give substantially pureA -3,7-diacetoxy- 9,11-epoxy-ergostadiene. Anal.-Calcd for CszH4aO5: C,74.96; H, 9.43. Found: C, 74.43; H, 9.17.

Example 3 Four hundred milligramsof A -3,7-diacetoxy-9,11-epoxy-ergostadiene, prepared substantially as described in Example 2hereinabove, was dissolved in aqueous methanol and the resultingsolution was allowed to stand for approximately 12 hours at roomtemperature. The crystalline material which separated in the form ofclusters of needles was recovered by filtration and dried to give 300mg. of A -3-acetoxy-7-keto-9Jl-epoxy-ergostene; M. P. 183192 C.

This material was recrystallized from methanol to give substantiallypure A -3-acetoxy-7-keto-9Jl-epoxy-ergostene; M. 194196 C. Anal.Calcdfor 0301-14604: C, 76.55; H, 9.85. Found: C, 76.48; H, 9.60.

Example 4 One hundred milligrams of A'-3,7-diacetoxy-9,1lepoxy-erg'ostadiene was dissolved in a 1 N solutionof sodium hydroxide in methanol, and the resulting solution was heatedunder reflux for a period of 1 hour. The resulting solution was dilutedwith water, and the 11 crystalline material which separated wasrecovered by filtration to give crude A-3,11-dihydrxy-7-keto-ergostadiene. This material was purified byrecrystallization from acetone to give 90 mg. of substantially pure A3,11-dihydroxy-7-keto-ergostadiene which was obtained in the formofsilky needles; M. P. 213-215 C.; a max.

255 mu; E% 191. (alcohol). Anal.-Caled for C28H4403Z C, 78.46; H 10.34.Found: C, 78.20; H, 10.24.

Example diacetoxy 7 keto ergostadiene; M. P. 176-177 C. Q

' Example'6 One hundred and sixty milligrams of A -3-acetoXy-7-keto-9,ll-epoxy-ergostene, prepared substantially. as described inExample 3 hereinabove, were dissolved in 10 cc. .ofacetone and to thissolution was added a solution containing 23 mg. rofrehromic acid in 1cc. of 2 N sulfuric. acid. The resulting mixture was allowed to react atroom temperature fora period of approximately 1 hour,

and the acetone was evaporated from the reaction turein vacuo. Theresidual'm aterial was diluted with water, and the crystalline materialwhich separated was recovered by,filtration and dried to give" crude A3- acetoxy:7,ll-diketo-ergostadiene; M! P. 115-126 C. This material wasrecrystallized from met'nanol to give 90 mg. of substantially pure A3-acetoxy-7,ll-diketoergostadiene; M. P. 135-136 C.; 7\ max. 265 mp; E%193 (iso-octane) Example 7 H30 CH3 C H:

O l l v i V V 011.000 1 cmooo a it I Compound 18 Compound 19 I i,Aqueous H 304 CH: CHI

I E0- 1 0 HO 0 v 1'1 1'1 1 Compound 20 Compound 21 I Acetic anhydrldAeetyl chloride H HQC CH: CH;

, V O Perbenzoic acid CHsCOQ l OGOCH: OH|GOO l OCOOH:

7 Compound 22 Compound 23 2334,99? 13 1'4 Aqueous l methanol HIC CH; CH;Ohromio acid CH) O O O O CHIOOO Compound 24 The A -bisdehydrotigogeninacetate epoxide utilized as the starting material in the followingexample can be prepared according to the procedure set forth in detailin co-pending applications Serial No. 213,807, filed March 3, 1951, andSerial No. 215,026, filed March 10, 1951. In that procedure, diosgenin-3acetate is reacted with N-bromosuccinimide and the resulting7-bromodiosgenin-3 acetate is heated with collidine thereby forming A-dehydrodiosgenin-3 acetate, the N-dehydrodiosgenin-3 acetate is reactedwith hydrogen in the presence of Raney nickel catalyst thereby formingN-dehydrotigogenin acetate, the latter compound is treated with mercuricacetate in glacial acetic acid to produce the A bisdehydrotigogeninacetate, and said A -bisdehydrotigogenin acetate is reacted withperbenzoic acid in benzene solution thereby forming the desired A'-bisdehydrotigogenin acetate ep oxide.

A hot solution of 1.0 g. of the A' -bisdchydrotigogenin acetate epoxide(Compounds 18 and 19) in 60 cc. of dioxane was diluted with cc. ofwater. Two cubic centimeters of a 2 N aqueous solution of sulfuric acidwas added to the aqueous dioxane solution, and the resulting mixture washeated to a temperature of about 90-100 C. for a period of approximately12 hours. At the end of this heating period, the reaction mixture wasevaporated substantially to dryness to give a mixture of A and-7-keto-dehydrotigogenin (Compounds 20 and 21). This mixture wasdissolved in a mixture of 20 cc. of acetic anhydride and 20 cc. ofacetyl chloride, and the resulting solution was heated under reflux fora period of about 4 hours. The solvents were removed from the reactionmixture by evaporation in vacuo to give the crude enol acetate, A-7-acetoxy-bisdehydrotigogenin acetate (Compound 22) This crude enolacetate was dissolved in cc. of benzene, and to this solution was added10 cc. of an 0.5 N solution of perbenzoic acid in benzene. The resultingmixture was allowed to stand at room temperature for approximately 6hours, and the benzene reaction solution was extracted with a suflicientquantity of a 2 N aqueous solution of sodium hydroxide to remove acidicproducts. The benzene solution was then dried and the solventsevaporated therefrom in vacuo to give A"-7-acetoxy-9,11-epoxy-dehydrotigogenin acetate (Compound 23).

The latter product was dissolved in 50 cc. of methanol containing 2 cc.of water, and the solution was allowed to stand at room temperature fora period of approximately 12 hours. The solvents were then evaporatedfrom this solution in vacuo to give 7-keto-9,11-epoxydehydrotigogeninacetate (Compound 24).

The latter product was dissolved in 50 cc. of acetone and to thesolution was added a solution containing 230 mg. of chromium trioxidedissolved in 10 cc. of 0.72 N aqueous sulfuric acid. The resultingmixture was allowed to stand at room temperature for a period of about 1hour. The reaction mixture was then diluted with water, and thecrystalline material which separated was recovered by filtration, driedand purified by recrystallization Compound 25 from methanol to givesubstantially pure A -7,11-diketodehydrotigogenin acetate (Compound 25);M. 1 .226- 227 C. a 14 (chloroform).

Example 8 Two grams of methyl A -3-acetoxy-choladienate epoxide (whichcan beprepared as described in co-pending application Serial No.215,026, filed March 10, 1951) were suspended in 20 cc. of aceticanhydride, and the suspension was heated in a sealed tube at atemperature of C. for a period of about four hours. The reactionsolution was cooled to room temperature whereupon large rectangularcrystalline plates separated from the solution. This crystallinematerial was recovered by filtration, washed with acetic anhydride anddried to give about 1.1 g. of crude methyl M -3-acetoxy-7-keto-cholnate;M. P. 168-170 C. This material was purified by chromatography followedby recrystallization from acetic anhydride to give substantially puremethyl A -3-acetoxy-7-keto-cholenate; M. P. C.

One gram of crude methyl A -3-acetoxy-7-ketocholenate, prepared asdescribed above, was dissolved with heating in 20 cc. of aceticanhydride and 20 cc. of acetyl chloride, and the solution was heatedunder reflux for about one hour. The reaction solution was evaporatedunder reduced pressure to give methyl A' -3,7-diacetoXy-choladienatewhich was obtained in the form of a syrup which absorbs in theultraviolet at 2430 A.;

l om. 252

Example 9 A suspension of 1.34 g. (0.003 mole) of methyl A3-acetoxy-choladienate epoxide in 20 cc. of acetic anhydride was heatedin a sealed tube at 150 C. for about four hours. Twenty cubiccentimeters of acetyl chloride was added to the reaction solution andthe resulting solution was heated at reflux temperature for a period ofapproximately one hour. The reaction solution was evaporated underreduced pressure to give 1.46 g. of methyl A' 3,7-diacetoXy-choladienatewhich was obtained in the form of a syrup which absorbs in theultraviolet at 2430 A.;

Example 10 The benzene reaction solution was extracted thereby removingacidic material, and the benzene layer was then extracted with wateruntil neutral. The benzene solution was dried over anhydrous sodiumsulfate and evaporated in vacuo to give methyl A -3,7-diacetoxy- 9,1l-epoxy-cholenate.

The methyl A' -3,7-diacetoxy-9,ll-epoxy-cholenate, prepared as describedabove, was dissolved in 7 cc. of 85% aqueous methanol and the solutionwas allowed to stand at room temperature for approximately twenty-fourhours. The solvent was then evaporated in vacuo and the residualmaterial was triturated with ether. The crystalline product wasrecovered by filtration and dried to give 0.14 g. of methyl A-3-acetoxy-7-ketol l-hydroxycholenate. tion from ethyl acetate to givesubstantially pure methyl A 3 acetoxy 7 keto 11 hydroxy cholenate; M. P.171-173 C. Anal.--Calcd for Carl-1400s: C, 70.40; H, 8.75. Found: C,70.37; H, 8.98. 7 max. 2540 A.,

as c. (chloroform).

Example 11 Thirty milligrams of chromium trioxide were dissolved in 0.3cc. of aqueous sulfuric acid, and the solution was added, with stirringat a temperature of about 20 C., to a solution containing 100 mg. ofmethyl A -3- acetoxy-7-keto-ll-hydroxy-cholenate dissolved in 10 cc. ofacetone. The resulting mixture was stirred at a temperature of 20 C. fora period of one hour, and the insoluble chromium residue was removed byfiltration and washed with a small volume of acetone. The filteredacetone solution and washings were added to 100 cc. of ice water, andthe crystalline material which precipitated was recovered by filtration,washed free of acid with water and dried to give 80 mg. of methyl A-3-acetoxy- 7,11-diketo-cholenate. This material was recrystallized fromethanol to give substantially pure methyl A 6-acetoxy-7-ll-diketo-cholenate; M. P. 114-115" C. Anal. Calcd forC21H3a0s: C, 70.70; H, 8.35. Found: C, 70.93; H, 8.30 [a]D =-|42(chloroform) '7 max. 2710 A.,

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of my invention.

I claim:

1. The process which comprises reacting A-7-ketocyclo-pentanopolyhydrophenanthrene with an acylating agentproduce the corresponding A'(11)-7-acyloxy-cyclopentanopolyhydrophenanthrene.

2. The process which comprises reacting A -S-hydroxy-7-keto-ergostadienewith an acetylating agent to produce A -3,7-diacetoXy-ergostatriene.

3. The process which comprises reacting M -7- keto dehydrotigogenin withan acetylating agent thereby producing A -7-acetoxy-bisdehydrotigogeninacetate.

4. The process which comprises reacting A' -7-acyloxy-cyclopentanopolyhydrophenanthrene with an organic per-acid toproduce the corresponding A -7-acyloxy- 9, 11-epoxy-cyclopentanopolyhydrophenanthrene.

5. The process which comprises reacting A' 3,7-diacetoxy-ergostatrienewith perbenzoic acid thereby forming A-3,7-diacetoxy-9,ll-epoxy-ergostadiene.

6. The process which comprises reacting A' -7-acetoxy-bisdehydrotigogenin with perbenzoic acid to produceA"-7-acetoxy-9,ll-epoxy-dehydrotigogenin acetate.

7. The process which comprises reacting methyl A3,7-diacetoxy-choladienate with perbenzoic acid to produce methyl A'-3,7-diacetoxy-9,1l-epoxy-cholenate.

This material was purified by recrystalliza :16 8. A'-3,7-diacctoiry-ergostatriene having the formula: 4

tlfi 1.0.... I

000cm v v 10. A -3,7-diacetoxy-9,1l-epoxy-ergostadiene having theformula:

p CHICOOQJO COCK! lit 11. A"-7-acetoxy-9,ll-epoxy-dehydrotigogeninacetate having the formula:

on, V p A V V CH;

CH;O0O

13. The process which comprises reacting M -7-keto-cyclopentanopolyhydrophenanthrene with an acylating agent toproduce the corresponding A fl-acyloxycyclopentanopolyhydrophenanthrene,and reacting the latter compound with an organic per-acid therebyforming the correspondingA"-7-acyloxy-9,1l-epoxy-cyclopentanopolyhydrophenanthrene. e V

14. The process which comprises reacting A -3-hy- 17droxy-7-keto-ergostadiene with an acetylating agent to produce A-3,7-diacetoXy-ergostatrine, and reacting this compound with perbenzoicacid, thereby forming A 3,7-diacetoxy-9,1 l-epoxy-ergostadiene.

15. The process which comprises reacting A -7-ket0- dehydrotigogeninwith an acetylating agent, thereby producing A-7-acetoxy-bisdehydrotigogenin acetate, and reacting this compound withperbenzoic acid to produce A -7-acetoxy-9,1 l-epoxy-dehydrotigogeninacetate.

16. The process which comprises reacting methyl A3-acetoxy-7-keto-cholenate with an acetylating agent to produce methyl A-3,7-diacetoxy-choladienate, and

18 reacting this compound with perbenzoic acid to produce methyl A-3,7-diacetoxy-9,1 l-epoxy-cholenate.

17. A 7 alkanoyloxy cyclopentanopolyhydrophenanthrene compounds selectedfrom the group which consists of A -3,7-di(loweralkanoyloxy)-ergostatricne, A -7-(lower alkanoyloxy)-bisdehydrotigogeninlower alkanoate, A -3-7-di(lower alkanoyloxy)-9,1lepoxy-ergostadiene, A'-7-(lower alkanoy10xy)-9,1l-epoxydehydrotigogenin lower alkanoate andlower alkyl 13 -3,-

10 7di(lower alkanoyloxy) -9,11-epoxy-cholenate.

No references cited.

17. $7 - 7 - ALKANOYLOXY - CYCLOPENTANOPOLYHYDROPHENANTHRENE COMPOUNDSSELECTED FROM THE GROUP WHICH CONSISTS OF $7,9(11),22-3,7-DI(LOWERALKANOYLOXY)-ERGOSTATRIENE, $7,9(11)-7-(LOWERALKANOYLOXY)-BISDEHYDROTIGOGENIN LOWER ALKANOATE, $7,22-3-7-DI(LOWERALKANOYLOXY)-9,11EPOXY-ERGOSTADIENE, $7-7-(LOWERALKANOYLOXY)-9,11-EPOXYDEHYDROTIGOGENIN LOWER ALKANOATE AND LOWER ALKYL$7-3,7-DI(LOWER ALKANOYLOXY)-9,11-EPOXY-CHOLENATE.